1. Field of the Invention
This invention relates to stable aromatic prostacyclin analogues which are active as inhibitors of blood platelet aggregation and which show arterial dilation activities.
2. Description of the Prior Art
The prostaglandins were first discovered in the 1920's and have proven since then to be among the most ubiquitous pharmaceutically active compounds ever tested. Their use and the use of analogues and derivatives thereof, has been suggested in as wide a range of applications as fertility control, induction of labor, regulation of blood pressure, regulation of blood clotting, control of asthma, anticonvulsion, antidepressing action and many others. A new compound has recently been discovered (Nature 263, 663 (1976); Prostaglandins, vol. 12, 685 and 715 (1976); Chem. and Engineering News, Dec. 20, 1976) which belongs to the general family of prostaglandins. The compound has been named prostacyclin and its structure has been proven by synthesis (Johnson, et. al, Prostaglandins, 12, 915 (1976); Corey, et al, J. Amer. Chem. Soc., 99, 2006 (1977) to be that of formula I. (The numbering system for prostacyclins is given for reference): ##STR3## Its generic name is 6,9.alpha.-oxido-11.alpha.,15.alpha.-dihydroxyprosta (Z)5, E(13)-dienoic acid. Prostacyclin is the most potent inhibitor of blood platelet aggregation of all the prostaglandins discovered to date. It has also been shown that prostacyclin destroys platelet aggregates after they have formed and that it has, in addition, a powerful action as a dilator of blood vessels. Prostacyclin thus appears to act in exactly opposite ways to thromboxane A.sub.2, another recently discovered member of the prostaglandin family. Thromboxane A.sub.2 causes platelet aggregation and simultaneously acts as powerful constrictor of arteries. Both prostacyclin and thromboxane A.sub.2 are derived biosynthetically from a common intermediate called endoperoxide, and they are decomposed by water to prostaglandins (Scheme I). The balance between the levels of prostacyclin and thromboxane A.sub.2, appears to maintain a finely tuned equilibrium between blood platelet aggregation versus dissolution and arterial constriction versus dilation. ##STR4##
Thromboxane A.sub.2 generated by platelets promotes aggregation while prostacyclin produced by vascular endothelium inhibits aggregation. It has also been proposed (S. Moncada et al, Lancet I, 18 (1977)) that (1) the basal formation of prostacyclin by vascular endothelium may be important in the maintenance of the normal integrity of vessel walls by inhibiting the adherence of platelets, (2 ) prostacyclin may normally limit thrombus formation, and (3) when a vessel wall is damaged, the formation of a normal hemostatic plug may be assisted by diminished prostacyclin production.
In addition to its effects on platelets, prostacyclin may play a crucial role in preventing gastric ulceration by inhibiting secretion, in blood pressure regulation by control of vascular tone, and in inflammation by inhibiting protease secretion of polymorphonuclear leucocytes. These and several other important physiological processes may be regulated by the opponent actions of thromboxane A.sub.2 (TXA.sub.2) and prostacyclin (PCI.sub.2). The use of prostacyclins has therefore been suggested in the treatment of blood clotting in diseased vessels of patients with cardiovascular problems. Since prostacyclin has retroactive action and not only inhibits blood clotting but also dissolves already formed clots, it can be used in heart attack cases and artherosclerosis. Increased susceptibility of platelets to aggregation accompanies vascular complications in diabetes, in cerebral strokes associated with essential hypertension and in post heart attack cases. These are other areas where prostacyclin or its analogues can be highly beneficial. The main drawback of the use of prostacyclin for these applications is its very short biological half-life of 2 minutes. This prevents the externally provided drug from reaching its target tissues intact. The need to maintain the drug in a totally anhydrous condition also prevents its ready shipment, storage and testing for pharmacological applications. If an analogue or derivative of prostacyclin can be found which is stable and shows similar effects on blood platelets and arteries, it would have wide applications in pharmacology and the treatment of cardiovascular and related diseases.
Another application for a stable analogue of prostacyclin would be its use as an inhibitor of blood platelet aggregation in externally circulated blood by kidney dialysis machines or heart-lung machines.
Prostacyclin analogues may also be useful in the treatment of several types of shock. For example, in hemorrhagic shock, vasoconstriction may severely limit the flow of blood to the gut and kidneys. Replacement of the blood volume lost will easily redilate the gut vessels but flow through the kidney may be impeded for a long period of time. During this interval the kidneys may infarct. In addition, prolonged vasoconstriction in the gut region may release proteases from liver and pancreatic lysozomes. Prostacyclin or its analogues may attenuate these deleterious effects by maintaining a small amount of blood flow through these areas.
A number of stable analogues of prostacyclin of varying biological activity has been prepared. See for example Nicolaou et al., Angew. Chem., Int. Ed. Engl. 17, 293 (1978) for a general review. Among these are thia-prostacyclins (II), discussed by Nicolaou and coworkers in J. Amer. Chem. Soc. 99, 7736 (1977). The thia-prostacyclins are also the subject of copending application Serial No. 886,141, filed Mar. 13, 1978 and which is herein incorporated by reference. ##STR5##
Another analogue of natural prostacyclin is .DELTA..sup.6 prostacyclin (.DELTA..sup.6 --PGI.sub.2, (III)) prepared by Shimoji and coworkers (J. Amer. Chem. Soc., 100, 2547 (1978). Compound III, .DELTA..sup.6 --PGI.sub.2, appears to have recently been isolated from rat stomach homogenates and its presumed structure was identified by Sih et al. (J. Amer. Chem. Soc., 100, 643 (1978)).
Upjohn scientists have recently reported the nitrogen-containing prostacyclin analogues IV and V; (Bundy, G., Tetrahedron Letters, 1371 (1978)): ##STR6##
Analogues IV and V showed high stability and potency in inhibiting platelet aggregation.
All of the aforementioned analogues (II-V) showed biological activity mimicking prostacyclin action. Other, somewhat less, active analogues of prostacyclin have also been prepared: dihydroprostacyclin (VI) (Corey et al, J. Amer. Chem. Soc, 99, 2006 (1977)) and (4E)--isoprostacyclin (VII), disclosed in U.S. application Ser. No. 886,143, filed Mar. 13, 1978. ##STR7##
The present inventors have compared the biological activity for all stable prostacyclin analogues reported to date (II-VII, plus others listed in the aforementioned Nicolaou et al article in Angewandte Chemie). They have sought to elucidate the structures which yield the highest biological activity and have discovered that the most potent ones are those retaining Sp.sup.2 --hybridized C-6. Natural prostacyclin, of course, contains an Sp.sup.2 hybridized C-6; compounds II-V do so as well. Compounds VI and VII on the other hand do not have a C-6 Sp.sup.2 -carbon and show less biological activity. Based on this discovery, the present inventors have discovered that both high stability and biological activity can be obtained generally when the labile cyclic ether rings of natural prostacyclin is replaced by a fully aromatic ring, a fact which among others assures the presence of an Sp.sup.2 hybridized C-6. The presence of an aromatic ring instead of a labile cyclic enol ether ring also ensures stability in aqueous, physiological media and renders the analogues useful for a large number of applications.